How a college student can derive the RNA world hypothesis from scratch

One of the greatest breakthroughs in twentieth century biology was the finding that RNA can serve as a catalyst and drive some of life’s essential chemical reactions. This discovery which garnered a Nobel Prize led the way to understanding ribozymes, splicing and the structure and function of the ribosome. It also propelled the conception of the so-called “RNA world hypothesis” for the origin of life which suggests that RNA was the earliest enzyme. This hypothesis in various forms has since been regarded as the single most plausible hypothesis for the origin of life.

The purpose of this post would be to postulate that, as stunning and important as the RNA world hypothesis is, it probably could be derived by a smart (admittedly a really smart) high-school or college student with no more than a basic understanding of organic chemistry, molecular biology and evolution. This exercise is in no way meant to be a put-down of the significance or difficulty of this discovery; on the contrary it illuminates the beautiful simplicity and logical nature of the hypothesis. The chain of reasoning can also be used as a pedagogic device to challenge students in chemistry and biology.

Let’s start with a fundamental question which a precocious college student might ask. “Why, if RNA is so unstable, does it serve as the genetic material at all?”. This question actually encapsulates the entire essence of the RNA world hypothesis. The instability of RNA is obvious from its chemical structure- RNA has two hydroxyl groups at the 2′ and 3′ positions on its ribose sugar. The problem is that the 2′ OH can serve as an internal nucleophile and break a 3′ phosphodiester bond as illustrated at the top of this post; in fact that’s precisely the reaction that RNA catalyzes in a ribozyme. The reaction is usually helped along by magnesium ions.

Thus, phosphodiester linkages in RNA are (relatively) quite unstable. DNA- deoxyribose as the name indicates- lacks the 2′ OH group and is therefore more stable. This makes it clear why RNA cannot serve as the original genetic material (DNA) but only as the messenger; the fidelity of information storage and transfer by the original genetic material is of such paramount importance that RNA would simply be too unstable to do the job. Evolution could entrust only DNA with the core function of being the blueprint of life.

So far so good, and a fine argument for why DNA and not RNA is the genetic storage disk. But then the question arises; why use RNA at all? The question is highlighted even more by the fact that while DNA functions in the nucleus, RNA transfers to the cytoplasm and performs the key function of protein synthesis. From a chemical standpoint, the cytoplasm is a much more hostile place than the nucleus, with several oxidizing, proteolytic and other kinds of enzymes waiting to chew up biomolecules. Entrusting the translation of genetic information in such a destructive environment to an unstable molecule like RNA sounds dangerously irresponsible of evolution.

But wait! The very instability of RNA that denies it the coveted function of the original genetic material also confers on it a marvelous capability of towering significance- catalytic ability. But why would you even think of catalysis in the first place? Well, the essence of evolution is the careful weighing of tradeoffs. If RNA is too unstable as the genetic material, it likely has some other property which compensates for this apparently deal-killing instability. At this point our intrepid college freshman will have to scratch her head and remember a few basics of enzyme catalysis. A little contemplation leads to the entirely reasonable hypothesis that enzyme catalysis needs at least two catalytic groups. Even if this hypothesis is wrong, it is still certainly true that two catalytic groups are better than one, and we have to remember than evolution is a greedy miser which can hungrily seize on any incremental advantage, no matter how small. Think of any kind of enzyme catalyzed reaction involving electron flow, say, the cleavage of peptide bonds by proteases. At the very least, you need one nucleophilic group to attack the peptide bond and another group (a positively charged one) to stabilize the resulting concentration of negative charge.

With this reasoning in hand, it is not too difficult for our admirable student to arrive at two great truths. Truth no. 1: In RNA, there are two hydroxyl groups. Truth no. 2: these groups are right next to each other. This is a really big deal. Our knowledge of enzymes tells us that proximity can greatly enhance reaction rate, sometimes by several orders of magnitude. This final capstone on the chain of thinking finally leads our precocious young adventurer to compile a succinct set of steps for arriving at the RNA world hypothesis through armchair speculation:

1. DNA is the original genetic material because RNA would have been too unstable. But then why does RNA exist at all?

2. The essence of evolution is tradeoffs. Perhaps RNA could have served another very important function that could have compensated for its instability?

3. One of the key steps in the origin of life was the capacity for chemical catalysis. Enzymatic reactions probably need at least two catalytic groups in close proximity to each other.

4. RNA with its two hydroxyl groups right next to each other could possibly function as a catalyst, in stark contrast to DNA which has only a single such group. This slight but all-important structural difference would have compensated for losses incurred due to instability and would have led RNA to transcend a barrier that was of superlative importance to the origin of life- the ability to bring about chemical reactions. QED.

Of course, the fundamental psychological barrier would still have been to think of something other than proteins acting as an enzyme. But this barrier is probably not as hard to surpass as we think. A hundred years before anything was known about the RNA world, giant chemical industries were already using metal-based catalysts to speed up reactions of great economic importance- the Haber-Bosch process being only one of many. If lowly metals could bring about such a diverse variety of reactions, then it’s not a long stretch to think of simple molecules unrelated to proteins doing the same.

There have been a handful of transformations that have been responsible for the ascendancy of life on this planet. The tiny modification that added a single hydroxyl group to RNA would probably rank at the very top. Rephrasing Robert Frost, two roads diverged in a wood, and I took the one with the 2′ hydroxyl group.

Our precocious youngster goes peacefully to sleep that night. She dreams of life on an RNA world.